THE EFFECT OF DITHIOCARBAMATES ON NEUROTOXIC ACTION OF 1-METHYL-4-PHENYL-1,2,3,6 TETRAHYDROPYRIDINE (MPTP) AND ON MITOCHONDRIAL RESPIRATIONCHAIN

The neurotoxin MPTP induces in human and in some laboratory animals pa rkinsonism-like neurological disorder, biochemically characterized by selective and irreversible decrease of dopamine content in striatum. T he terminal step in the mechanism of neurotoxic action of MPTP is the inhibition of mitochondrial respiratory chain by pyridinium metabolite (MPP+) resulting in energy depletion and nervous cells death. Earlier it was shown that some chemical compounds, in particular diethyldithi ocarbamate (DTC), can potentiate MPTP neurotoxicity. In the present wo rk we have studied the influence of DTC derivatives on MPTP neurotoxic effect in vivo and on MPP+ inhibition of mitochondrial respiration (b oth on intact mitochondria and on submitochondrial particles) in vitro . It was revealed that DTC alone change mitochondrial membrane state b y respiratory chain uncoupling and inhibition. DTC and MPP+ mutually p otentiate inhibition of electron Transport as well. The combined effec t of DTC plus MPP+ action on mitochondria respiration reflects the sum of reciprocally leveling and potentia ting factors and can explain th e order of efficacy of MPTP-neurotoxicity potentiation in vivo in seri es of close DTC derivatives. (C) 1996 Intox Press, Inc.